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Comment by Dr. Krishna Kumari Challa on September 16, 2021 at 9:46am

Differences in cellular signaling offer clues to insulin resistance

In what could be a starting point for new therapeutics to tackle insulin resistance, a major driver of type 2 diabetes and metabolic syndrome present in 20–30 percent of the general U.S. population, researchers recently found that insulin resistance in the general population seems likely to be caused by a series of cell-specific signaling defects, some of which appear to be sex specific.

In addition, only a portion of the defects are shared with those seen in diabetes, pointing towards the existence of novel pathways behind insulin resistance in the general population.

Most people know that insulin is an important hormone for controlling blood glucose, but most people don't realize how important insulin is for all aspects of metabolism—not just sugar, but lipids, amino acids, and proteins

Insulin resistance, that is the failure of the body to respond normally to insulin, is very common in the population, not just in people with diabetes or obesity, and these individuals are at high risk for developing these metabolic disorders.

The research is based on a stem-cell modeling system called iMyos that can be used to investigate cell-specific changes in signaling in combination with a technique called phosphoproteomics.

Specifically, the researchers used stem cells derived from blood cells of individuals without diabetes who were either insulin sensitive or resistant.

The researchers could then investigate differences in cellular signaling, both in the absence and presence of insulin stimulation, to determine how insulin resistance or sensitivity affected signaling in a series of different pathways.

In what emerges as a complex picture, they found large differences in phosphoproteome signatures based on insulin sensitivity status but also based on the sex of the cell donors.

Nida Haider et al, Signaling defects associated with insulin resistance in non-diabetic and diabetic individuals and modification by sex, Journal of Clinical Investigation (2021). DOI: 10.1172/JCI151818

Part 1

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Comment by Dr. Krishna Kumari Challa on September 16, 2021 at 9:36am

How to modify RNA: Crucial steps for adding chemical tag to transfer RNA revealed

The chemical steps in an important cellular modification process that adds a chemical tag to some RNAs have been revealed in a new study. Interfering with this process in humans can lead to neuronal diseases, diabetes, and cancers. A research team has imaged a protein that facilitates this RNA modification in bacteria, allowing the researchers to reconstruct the process. A paper describing the modification process appears Sept. 15 in the journal Nature.

Transfer RNAs (tRNA) are the RNAs that "read" the genetic code and translate it into a sequence of amino acids to make a protein. The addition of a chemical tag—a methyl sulfur group—to a particular location on some tRNAs improves their ability to translate messenger RNA into proteins. When this modification process—called methylthiolation—doesn't occur properly, mistakes can be incorporated into the resulting proteins, which in humans can lead to neuronal disease, cancer, and increased risk of developing Type 2 diabetes.

Methylthiolation is ubiquitous across bacteria, plants, and animals. In this study, researchers  determined the structure of a protein called MiaB to better understand its role in facilitating this important modification process in bacteria.

Structural basis for tRNA methylthiolation by the radical SAM enzyme MiaB, Nature (2021). DOI: 10.1038/s41586-021-03904-6 , www.nature.com/articles/s41586-021-03904-6

https://phys.org/news/2021-09-rna-crucial-adding-chemical-tag.html?...

Comment by Dr. Krishna Kumari Challa on September 15, 2021 at 10:41am

Diamonds beneath our feet

There might be a quadrillion tons of diamonds 100 miles below Earth’s surface. But the furthest we’ve traveled is 7 miles down, so how could we know that?

Comment by Dr. Krishna Kumari Challa on September 15, 2021 at 10:07am

Chemically masked cytokines and antibodies turn active selectively in tumors as safer cancer immunotherapies. Credit: Yu Zhao 2021 EPFL

Comment by Dr. Krishna Kumari Challa on September 15, 2021 at 10:03am

New immunotherapy method turns activated specifically in tumor

Immunotherapy drugs are promising new weapons in the fight against cancer, but they are so strong that they can be toxic to the rest of the human body. The basic idea behind immunotherapy drugs is simple. Doctors inject special kinds of drugs, especially proteins such as antibodies and cytokines prepared or modified in a lab, into a patient, where they activate the patient’s immune cells –T-cells, NK cells, and so on – and help these cells fight the tumor. In short, immunotherapy drugs work like a powerful cocktail that boosts a patient’s own immune system.

After being prescribed by a doctor, immunotherapy drugs are administered intravenously.

Once inside the body, the drugs spread all over – not just where the tumor or any metastases are located. The problem is that the proteins in the drugs are so strong that they damage healthy tissue. Many of the immunotherapy treatments already out there have proven to be highly effective against cancer in preclinical studies. But they often can’t be used to save people because they’re too toxic to the rest of the body. The treatments that are used in patients today have been toned down so they’re less potent. That makes them safer, but also less effective at destroying tumors. The aim of this new method is to keep all the potency of immunotherapy, because it will be an important treatment option for cancer patients.
Researchers, therefore, developed a method whereby the immunotherapy proteins are activated only when they come into the tumor tissues.  This method draws on techniques from both chemistry and immune engineering.

The tumor microenvironment is different from the rest of the body. The pH is lower, meaning it’s more acidic, and it has a high reducing potential. Researchers used these facts, already known to scientists, to develop a kind of polymer shield for the protein drugs that would let them travel harmlessly through the body until they reach the tumor.

That shield is designed to break down when exposed to the unique chemical environment in the tumor tissue. Chemical reactions in the tumour microenvironment break the bonds at the protein surface, thereby removing the polymer shield. The protein drugs are then free to activate the patient’s cancer-fighting lymphocytes selectively in the tumour tissue.

Zhao, Y. ; Xie, Y.-Q. ; Van Herck, S. ; Nassiri, S. ; Gao, M. ; Guo...

https://actu.epfl.ch/news/new-immunotherapy-becomes-activated-speci...

https://www.myscience.ch/en/news/2021/new_immunotherapy_becomes_act...

https://researchnews.cc/news/8892/New-immunotherapy-method-turns-ac...

Comment by Dr. Krishna Kumari Challa on September 15, 2021 at 9:49am

Scientists pinpoint the uncertainty of our working memory

The human brain regions responsible for working memory content are also used to gauge the quality, or uncertainty, of memories, a team of scientists has found. Its study uncovers how these neural responses allow us to act and make decisions based on how sure we are about our memories.

Access to the uncertainty in our working memory enables us to determine how much to 'trust' our memory in making decisions.

This research is the first to reveal that the neural populations that encode the content of working memory also represent the uncertainty of memory.

Working memory, which enables us to maintain information in our minds, is an essential cognitive system that is involved in almost every aspect of human behavior—notably decision-making and learning.

For example, when reading, working memory allows us to store the content we just read a few seconds ago while our eyes keep scanning through the new sentences. Similarly, when shopping online, we may compare, "in our mind," the item in front of us on the screen with previous items already viewed and still remembered.

"It is not only crucial for the brain to remember things, but also to weigh how good the memory is: How certain are we that a specific memory is accurate?

 The study results yielded the first evidence that the human brain registers both the content and the uncertainty of working memory in the same cortical regions.

The knowledge of uncertainty of memory also guides people to seek more information when we are unsure of our own memory.

Joint representation of working memory and uncertainty in human cortex, Neuron (2021). DOI: 10.1016/j.neuron.2021.08.022

https://medicalxpress.com/news/2021-09-scientists-uncertainty-memor...

Comment by Dr. Krishna Kumari Challa on September 15, 2021 at 9:45am

Researchers find immune cells that guard frequent site of cancer spread

In the progressing field of immunotherapy, surprisingly little is known about immunity to metastatic tumors in locations such as lymph nodes, a frequent place where cancers first spread. Not only do lymph nodes act as a gateway for cancer cells to travel throughout the body, but they are also home to infection-fighting white blood cells called T cells. In some cases, T cells in lymph nodes activate to kill invading cancer cells. In other cases, that process clearly fails.

While T cells can freely travel from lymph nodes into the bloodstream and back to the lymph nodes, researchers in Turk's lab have discovered a novel population of tumor-fighting T cells that do not circulate, but rather stay in lymph nodes where they provide protection against melanoma. "These T cells, for whatever reason, have changed their program and stay in the lymph nodes where they persist and kill tumor cells for many months while never entering circulation," says Turk.

These long-lived T cells, called "lymph node resident memory T cells," were shown to counteract melanoma spreading in mice. Turk's team found that when melanoma cells were put back into mice that had been cured of cancer with immunotherapy a month earlier, the lymph nodes were still resistant to the cancer—the melanoma would not grow.

Researchers identified T cells with similar characteristics in melanoma-invaded patient lymph nodes, showing that similar populations exist in humans.

Computational analysis of melanoma specimen data from The Cancer Genome Atlas revealed that the presence of T cells with this gene signature predicted better outcomes and improved survival for human melanoma patients with lymph node metastases. "These studies reveal a new population of T cells that is vital for counteracting the earliest stages of cancer metastasis.

Resident memory T cells in regional lymph nodes mediate immunity to metastatic melanoma, Immunity, DOI: 10.1016/j.immuni.2021.08.019

https://medicalxpress.com/news/2021-09-immune-cells-frequent-site-c...

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Comment by Dr. Krishna Kumari Challa on September 15, 2021 at 9:10am

In some cases, the presence of those newly detected autoantibodies may reflect an increase, driven by the immune response, of antibodies that had been flying under the radar at low levels, Utz said. It could be that inflammatory shock to the systems of patients with severe COVID-19 caused a jump in previously undetectable, and perhaps harmless, levels of autoantibodies these individuals may have been carrying prior to infection.

In other cases, autoantibody generation could result from exposure to viral materials that resemble our own proteins.

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It's possible that, in the course of a poorly controlled SARS-CoV-2 infection—in which the virus hangs around for too long while an intensifying immune response continues to break viral particles into pieces—the immune system sees bits and pieces of the virus that it hadn't previously seen," he said. "If any of these viral pieces too closely resemble one of our own proteins, this could trigger autoantibody production."

The finding bolsters the argument for vaccination. Vaccines for COVID-19 contain only a single protein—SARS-CoV-2's so-called spike protein—or the genetic instructions for producing it. With vaccination, the immune system is never exposed to—and potentially confused by—the numerous other novel viral proteins generated during infection.

In addition, vaccination is less intensely inflammatory than an actual infection, so there's less likelihood that the immune system would be confused into generating antibodies to its own signaling proteins or to the body's own tissues.

Patients who, in response to vaccination, quickly mount appropriate antibody responses to the viral spike protein should be less likely to develop autoantibodies.

Indeed, a recent study in Nature showed that, unlike SARS-CoV-2 infection, the COVID-19 vaccine produced by Pfizer doesn't trigger any detectable generation of autoantibodies among recipients.

1. Sarah Esther Chang, Allan Feng, Wenzhao Meng, Sokratis A. Apostolidis, Elisabeth Mack, Maja Artandi, Linda Barman, Kate Bennett, Saborni Chakraborty, Iris Chang, Peggie Cheung, Sharon Chinthrajah, Shaurya Dhingra, Evan Do, Amanda Finck, Andrew Gaano, Reinhard Geßner, Heather M. Giannini, Joyce Gonzalez, Sarah Greib, Margrit Gündisch, Alex Ren Hsu, Alex Kuo, Monali Manohar, Rong Mao, Indira Neeli, Andreas Neubauer, Oluwatosin Oniyide, Abigail E. Powell, Rajan Puri, Harald Renz, Jeffrey Schapiro, Payton A. Weidenbacher, Richard Wittman, Neera Ahuja, Ho-Ryun Chung, Prasanna Jagannathan, Judith A. James, Peter S. Kim, Nuala J. Meyer, Kari C. Nadeau, Marko Radic, William H. Robinson, Upinder Singh, Taia T. Wang, E. John Wherry, Chrysanthi Skevaki, Eline T. Luning Prak, Paul J. Utz. New-onset IgG autoantibodies in hospitalized patients with COVID-19. Nature Communications, 2021; 12 (1) DOI: 10.1038/s41467-021-25509-3

https://medicalxpress.com/news/2021-09-links-severe-covid-self-atta...

part 2

Comment by Dr. Krishna Kumari Challa on September 15, 2021 at 9:08am

Study links severe COVID-19 to increase in self-attacking antibodies

Hospitalized COVID-19 patients are substantially more likely to harbor autoantibodies—antibodies directed at their own tissues or at substances their immune cells secrete into the blood—than people without COVID-19, according to a new study.

Autoantibodies can be early harbingers of full-blown autoimmune disease.

If you get sick enough from COVID-19 to end up in the hospital, you may not be out of the woods even after you recover.

The scientists looked for autoantibodies in blood samples drawn during March and April of 2020 from 147 COVID-19 patients at the three university-affiliated hospitals and from a cohort of 48 patients at Kaiser Permanente in California. Blood samples drawn from other donors prior to the COVID-19 pandemic were used as controls.

The researchers identified and measured levels of antibodies targeting the virus; autoantibodies; and antibodies directed against cytokines, proteins that immune cells secrete to communicate with one another and coordinate their overall strategy.

Upward of 60% of all hospitalized COVID-19 patients, compared with about 15% of healthy controls, carried anti-cytokine antibodies, the scientists found. This could be the result of immune-system overdrive triggered by a virulent, lingering infection. In the fog of war, the abundance of cytokines may trip off the erroneous production of antibodies targeting them.

If any of these antibodies block a cytokine's ability to bind to its appropriate receptor, the intended recipient immune cell may not get activated. That, in turn, might buy the virus more time to replicate and lead to a much worse outcome.

Part1

Comment by Dr. Krishna Kumari Challa on September 15, 2021 at 8:55am

People only pay attention to new information when they want to

A new paper in the Journal of the European Economic Association, published by Oxford University Press, indicates that we tend to listen to people who tell us things we'd like to believe and ignore people who tell us things we'd prefer not to be true. As a result, like-minded people tend to make one another more biased when they exchange beliefs with one another.

While it would reasonable to think that people form decisions based on evidence and experience alone, previous research has demonstrated that decision makers have "motivated beliefs;" They believe things in part because they would like such things to be true. Motivated beliefs (and the reasoning that leads to them) can generate serious biases. Motivated beliefs have been speculated to explain the proliferation of misinformation on online forums.

The experiment conducted supports a lot of popular suspicions about why biased beliefs might be getting worse in the age of the internet. We now get a lot of information from social media and we don't know much about the quality of the information we're getting. As a result, we're often forced to decide for ourselves how accurate various opinions and sources of information are and how much stock to put in them. Our results suggest that people resolve this quandary by assigning credibility to sources that are telling us what we'd like to hear and this can make biases due to motivated reasoning a lot worse over time.

Ryan Oprea et al, Social Exchange of Motivated Beliefs, Journal of the European Economic Association (2021). DOI: 10.1093/jeea/jvab035

https://phys.org/news/2021-09-people-attention.html?utm_source=nwle...

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